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152. Differences in Steap3 expression are a mechanism of genetic variation of RBC storage and oxidative damage in mice

Author

Howie, Heather L., primary, Hay, Ariel M., additional, de Wolski, Karen, additional, Waterman, Hayley, additional, Lebedev, Jenna, additional, Fu, Xiaoyun, additional, Culp-Hill, Rachel, additional, D’Alessandro, Angelo, additional, Gorham, James D., additional, Ranson, Matthew S., additional, Roback, John D., additional, Thomson, Peter C., additional, and Zimring, James C., additional

Published
2019
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155. Reexamination of the chromium‐51–labeled posttransfusion red blood cell recovery method

Author

Francis, Richard O., primary, Mahajan, Sonia, additional, Rapido, Francesca, additional, La Carpia, Francesca, additional, Soffing, Mark, additional, Divgi, Chaitanya, additional, Yeh, Randy, additional, Mintz, Akiva, additional, Leslie, Lenhurst, additional, Agrest, Irina, additional, Karafin, Matthew S., additional, Ginzburg, Yelena, additional, Shaz, Beth H., additional, Spitalnik, Steven L., additional, Schwartz, Joseph, additional, Thomas, Tiffany, additional, Fu, Xiaoyun, additional, Amireault, Pascal, additional, Buffet, Pierre, additional, Zimring, James C., additional, D'Alessandro, Angelo, additional, and Hod, Eldad A., additional

Published
2019
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159. Increased Methylation of Deamidated Asparagines and Aspartates in Stored Red Blood Cells from Glucose 6-Phosphate Dehydrogenase-Deficient Blood Donors

Author

D'Alessandro, Angelo, primary, Nemkov, Travis, additional, Reisz, Julie, additional, Dzieciatkowska, Monika, additional, Culp-Hill, Rachel, additional, Stefanoni, Davide, additional, Yoshida, Tatsuro, additional, Dunham, Andrew, additional, Kanias, Tamir, additional, DuMont, Larry J., additional, Busch, Michael Paul, additional, Eisenmesser, Elan Z, additional, Hansen, Kirk C, additional, Fu, Xiaoyun, additional, Thomas, Tiffany, additional, Karafin, Matthew, additional, Hod, Eldad A., additional, Francis, Richard O, additional, Spitalnik, Steven L, additional, and Zimring, James C., additional

Published
2018
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161. Methylation of protein aspartates and deamidated asparagines as a function of blood bank storage and oxidative stress in human red blood cells

Author

Reisz, Julie A., primary, Nemkov, Travis, additional, Dzieciatkowska, Monika, additional, Culp-Hill, Rachel, additional, Stefanoni, Davide, additional, Hill, Ryan C., additional, Yoshida, Tatsuro, additional, Dunham, Andrew, additional, Kanias, Tamir, additional, Dumont, Larry J., additional, Busch, Michael, additional, Eisenmesser, Elan Z., additional, Zimring, James C., additional, Hansen, Kirk C., additional, and D'Alessandro, Angelo, additional

Published
2018
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162. In utero exposure to alloantigens primes alloimmunization to platelet transfusion in mice.

Author

Poston, Jacqueline N., Jash, Arijita, Hannan, Lindsay M., Hay, Ariel M., Usaneerungrueng, Chomkan, Howie, Heather L., Kapp, Linda M., and Zimring, James C.

Subjects
BLOOD platelet transfusion, HLA histocompatibility antigens, MAJOR histocompatibility complex, ANTIBODY titer, MICE
Abstract

Background: Platelet transfusions remain a mainstay of treatment for many patients with thrombocytopenia, but can lead to alloantibodies to Human Leukocyte Antigens (anti‐HLA) resulting in inadequate responses to subsequent platelet transfusions (refractoriness), as well as complicate transplantation. Despite substantial decreases in alloimmunization with the implementation of leukoreduction, a significant percentage of patients still become alloimmunized following platelet transfusions. It remains unclear why some patients make anti‐HLA antibodies, but others do not make anti‐HLA antibodies even with chronic transfusion. Antecedent pregnancy correlates with risk of alloimmunization due to platelet transfusion in humans ‐ however, isolation of pregnancy as a single variable is not possible in human populations. Study Design and Methods: A tractable murine model of pregnancy and transfusion was engineered by breeding C57BL/6 (H‐2b) dames with BALB/c (H‐2d) sires. After pregnancy, female mice were transfused with leukoreduced platelets from F1 (H‐2b/d) donors that expressed the same paternal major histocompatibility complex (MHC) H‐2d alloantigens as the sires. Control groups allowed isolation of pregnancy or transfusion alone as independent variables. Alloimmunization was determined by testing serum for antibodies to H‐2d MHC alloantigens. Results: No alloantibodies were detected after pregnancy alone, or in response to transfusion of platelets alone; however, significant levels of alloantibodies were detected when pregnancy was followed by transfusion. Conclusions: These findings isolate antecedent pregnancy as a causal contribution to increased frequencies of alloimmunization by subsequent platelet transfusion in mice and provide a platform for ongoing mechanistic investigation. [ABSTRACT FROM AUTHOR]

Published
2021
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164. Iron-deficient erythropoiesis in blood donors and red blood cell recovery after transfusion: initial studies with a mouse model

Author

Bandyopadhyay, Sheila, Brittenham, Gary M., Francis, Richard O., Zimring, James C., Hod, Eldad A., and Spitalnik, Steven L.

Subjects
Mice, Erythrocytes, Anemia, Iron-Deficiency, Iron, Animals, Humans, Original Article, Blood Donors, Erythropoiesis, Iron Deficiencies, Recovery of Function
Abstract

Most frequent red cell (RBC) donors and many first-time donors are iron deficient, but meet haemoglobin standards. However, the effects of donation-induced iron deficiency on RBC storage quality are unknown. Thus, we used a mouse model to determine if donor iron deficiency reduced post-transfusion RBC recovery.Weanling mice received a control diet or an iron-deficient diet. A third group receiving the iron-deficient diet was also phlebotomised weekly. This provided 3 groups of mice with different iron status: (1) iron replete, (2) mild iron deficiency with iron-deficient erythropoiesis, and (3) iron-deficiency anaemia. At ten weeks of age, blood was collected, leucoreduced, and stored at 4 ºC. After 12 days of storage, 24-hour (h) post-transfusion RBC recovery was quantified in recipients by flow cytometry.Before blood collection, mean haemoglobin concentrations in the iron-replete, iron-deficient, and iron-deficiency anaemia donor mice were 16.5±0.4, 11.5±0.4, and 7.0±1.4 [g/dL± 1 standard deviation (SD)], respectively (p0.01 for all comparisons between groups). The 24-h post-transfusion RBC recoveries in recipients receiving transfusions from these three cohorts were 77.1±13.2, 66.5±10.9, and 46.7±15.9 (% ±1 SD), respectively (p0.05 for all comparisons between groups).In summary, donor iron deficiency significantly reduced 24-h post-transfusion RBC recovery in recipient mice. RBCs from mice with mild iron deficiency and iron-deficient erythropoiesis, with haemoglobin levels similar to those used for human autologous blood donation, had intermediate post-transfusion RBC recovery, as compared to iron-replete donors and those with iron-deficiency anaemia. This suggests that, in addition to the effects of iron deficiency on donor health, frequent blood donation, leading to iron-deficient erythropoiesis, may also have adverse effects for transfusion recipients.

Published
2017

165. Stored RBC metabolism as a function of caffeine levels.

Author

D'Alessandro, Angelo, Fu, Xiaoyun, Reisz, Julie A., Kanias, Tamir, Page, Grier P., Stone, Mars, Kleinman, Steve, Zimring, James C., Busch, Michael, and Recipient Epidemiology and Donor Evaluation Study-III (REDS III)

Subjects
ERYTHROCYTE metabolism, ENERGY metabolism, BIOCHEMISTRY, COFFEE, BLOOD collection, XANTHINE, CAFFEINE, GLYCOLYSIS
Abstract

Background: Coffee consumption is extremely common in the United States. Coffee is rich with caffeine, a psychoactive, purinergic antagonist of adenosine receptors, which regulate red blood cell energy and redox metabolism. Since red blood cell (purine) metabolism is a critical component to the red cell storage lesion, here we set out to investigate whether caffeine levels correlated with alterations of energy and redox metabolism in stored red blood cells.Study Design and Methods: We measured the levels of caffeine and its main metabolites in 599 samples from the REDS-III RBC-Omics (Recipient Epidemiology Donor Evaluation Study III Red Blood Cell-Omics) study via ultra-high-pressure-liquid chromatography coupled to high-resolution mass spectrometry and correlated them to global metabolomic and lipidomic analyses of RBCs stored for 10, 23, and 42 days.Results: Caffeine levels positively correlated with increased levels of the main red cell antioxidant, glutathione, and its metabolic intermediates in glutathione-dependent detoxification pathways of oxidized lipids and sugar aldehydes. Caffeine levels were positively correlated with transamination products and substrates, tryptophan, and indole metabolites. Expectedly, since caffeine and its metabolites belong to the family of xanthine purines, all xanthine metabolites were significantly increased in the subjects with the highest levels of caffeine. However, high-energy phosphate compounds ATP and DPG were not affected by caffeine levels, despite decreases in glucose oxidation products-both via glycolysis and the pentose phosphate pathway.Conclusion: Though preliminary, this study is suggestive of a beneficial correlation between the caffeine levels and improved antioxidant capacity of stored red cells. [ABSTRACT FROM AUTHOR]

Published
2020
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166. Ethyl glucuronide, a marker of alcohol consumption, correlates with metabolic markers of oxidant stress but not with hemolysis in stored red blood cells from healthy blood donors.

Author

D'Alessandro, Angelo, Fu, Xiaoyun, Reisz, Julie A., Stone, Mars, Kleinman, Steve, Zimring, James C., Busch, Michael, and Recipient Epidemiology and Donor Evaluation Study-III (REDS III)

Subjects
ERYTHROCYTE metabolism, RESEARCH, HEMOLYSIS & hemolysins, RESEARCH methodology, BLOOD collection, MEDICAL cooperation, EVALUATION research, OXIDATIVE stress, COMPARATIVE studies, ALCOHOL drinking, RESEARCH funding, ACYCLIC acids
Abstract

Background: Red blood cell (RBC) storage in the blood bank is associated with the progressive accumulation of oxidant stress. While the mature erythrocyte is well equipped to cope with such stress, recreative habits like alcohol consumption may further exacerbate the basal level of oxidant stress and contribute to the progress of the storage lesion.Study Design and Methods: RBC levels of ethyl glucuronide, a marker of alcohol consumption, were measured via ultra-high-pressure liquid chromatography coupled with high-resolution mass spectrometry. Analyses were performed on 599 samples from the recalled donor population at Storage Days 10, 23, and 42 (n = 250), as part of the REDS-III RBC-Omics (Recipient Epidemiology Donor Evaluation Study III Red Blood Cell-Omics) study. This cohort consisted of the 5th and 95th percentile of donors with extreme hemolytic propensity out of the original cohort of 13,403 subjects enrolled in the REDS-III RBC Omics study. Ehtyl glucuronide levels were thus correlated to global metabolomics and lipidomics analyses and RBC hemolytic propensity.Results: Ethyl glucuronide levels were positively associated with oxidant stress markers, including glutathione consumption and turnover, methionine oxidation, S-adenosylhomocysteine accumulation, purine oxidation, and transamination markers. Decreases in glycolysis and energy metabolism, the pentose phosphate pathway and ascorbate system were observed in those subjects with the highest levels of ethyl glucuronide, though hemolysis values were comparable between groups.Conclusion: Though preliminary, this study is suggestive that markers of alcohol consumption are associated with increases in oxidant stress and decreases in energy metabolism with no significant impact on hemolytic parameters in stored RBCs from healthy donor volunteers. [ABSTRACT FROM AUTHOR]

Published
2020
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170. Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016

Author

Vostal, Jaroslav G., primary, Buehler, Paul W., additional, Gelderman, Monique P., additional, Alayash, Abdu I., additional, Doctor, Alan, additional, Zimring, James C., additional, Glynn, Simone A., additional, Hess, John R., additional, Klein, Harvey, additional, Acker, Jason P., additional, Spinella, Philip C., additional, D'Alessandro, Angelo, additional, Palsson, Bernhard, additional, Raife, Thomas J., additional, Busch, Michael P., additional, McMahon, Timothy J., additional, Intaglietta, Marcos, additional, Swartz, Harold M., additional, Dubick, Michael A., additional, Cardin, Sylvain, additional, Patel, Rakesh P., additional, Natanson, Charles, additional, Weisel, John W., additional, Muszynski, Jennifer A., additional, Norris, Philip J., additional, and Ness, Paul M., additional

Published
2017
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173. Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

Author

Nemkov, Travis, primary, Sun, Kaiqi, additional, Reisz, Julie A., additional, Song, Anren, additional, Yoshida, Tatsuro, additional, Dunham, Andrew, additional, Wither, Matthew J., additional, Francis, Richard O., additional, Roach, Robert C., additional, Dzieciatkowska, Monika, additional, Rogers, Stephen C., additional, Doctor, Allan, additional, Kriebardis, Anastasios, additional, Antonelou, Marianna, additional, Papassideri, Issidora, additional, Young, Carolyn T., additional, Thomas, Tiffany A., additional, Hansen, Kirk C., additional, Spitalnik, Steven L., additional, Xia, Yang, additional, Zimring, James C., additional, Hod, Eldad A., additional, and D’Alessandro, Angelo, additional

Published
2017
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174. Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress and disease

Author

Kanias, Tamir, Sinchar, Derek, Osei-Hwedieh, David, Baust, Jeffrey J., Jordan, Andrew, Zimring, James C., Waterman, Hayley R, de Wolski, Karen S, Acker, Jason P., and Gladwin, Mark T.

Subjects
Adult, Male, Canada, Erythrocytes, Age Factors, Mice, Inbred Strains, Middle Aged, Hemolysis, Article, United States, Mice, Oxidative Stress, Sex Factors, Blood Preservation, Osmotic Pressure, Animals, Humans, Female, Testosterone
Abstract

Red blood cell (RBC) hemolysis represents an intrinsic mechanism for human vascular disease. Intravascular hemolysis releases hemoglobin and other metabolites that inhibit nitric oxide signaling and drive oxidative and inflammatory stress. Although these pathways are important in disease pathogenesis, genetic and population modifiers of hemolysis, including sex, have not been established.We studied sex differences in storage or stress-induced hemolysis in RBC units from the United States and Canada in 22 inbred mouse strains and in patients with sickle cell disease (SCD) using measures of hemolysis in 315 patients who had homozygous SS hemoglobin from the Walk-PHASST cohort. A mouse model also was used to evaluate posttransfusion recovery of stored RBCs, and gonadectomy was used to determine the mechanisms related to sex hormones.An analysis of predisposition to hemolysis based on sex revealed that male RBCs consistently exhibit increased susceptibility to hemolysis compared with females in response to routine cold storage, under osmotic or oxidative stress, after transfusion in mice, and in patients with SCD. The sex difference is intrinsic to the RBC and is not mediated by plasmatic factors or female sex hormones. Importantly, orchiectomy in mice improves RBC storage stability and posttransfusion recovery, whereas testosterone repletion therapy exacerbates hemolytic response to osmotic or oxidative stress.Our findings suggest that testosterone increases susceptibility to hemolysis across human diseases, suggesting that male sex may modulate clinical outcomes in blood storage and SCD and establishing a role for donor genetic variables in the viability of stored RBCs and in human hemolytic diseases.

Published
2016

175. Serological blind spots for variants of human IgG3 and IgG4 by a commonly used anti-immunoglobulin reagent

Author

Howie, Heather L., Delaney, Meghan, Wang, Xiaohong, Er, Lay See, Vidarsson, Gestur, Stegmann, Tamara C, Kapp, Linda, Lebedev, Jenna N., Wu, Yanyun, AuBuchon, James P., Zimring, James C., Landsteiner Laboratory, and Graduate School

Subjects
Histocompatibility Testing, Racial Groups, Antibodies, Monoclonal, Genetic Variation, Article, Antibodies, Anti-Idiotypic, Isoantibodies, Immunoglobulin G, parasitic diseases, Animals, Humans, Rabbits, Diagnostic Errors, Immunoglobulin Allotypes
Abstract

Human immunoglobulin G (IgG) includes four different subtypes (IgG1, IgG2, IgG3, and IgG4), and it is also now appreciated that there are genetic variations within IgG subtypes (called isoallotypes). Twenty-nine different isoallotypes have been described, with 7, 4, 15, and 3 isoallotypes described for IgG1, IgG2, IgG3, and IgG4, respectively. The reactivity of anti-IgG with different isoallotypes has not been characterized. A novel monoclonal anti-K antibody (PugetSound Monoclonal Antibody 1 [PUMA1]) was isolated and sequenced, and a panel of PUMA1 variants was expressed, consisting of the 29 known IgG isoallotypes. The resulting panel of antibodies was preincubated with K-positive red blood cells (RBCs) and then subjected to testing with currently approved anti-IgG by flow cytometry, solid phase systems, gel cards, and tube testing. A US Food and Drug Administration (FDA)-approved monoclonal anti-IgG (gamma-clone) failed to recognize 2 of 15 IgG3 isoallotypes (IgG3-03 and IgG3-13) and 3 of 3 IgG4 isoallotypes (IgG4-01, IgG4-02, and IgG4-03). In contrast, an FDA-approved rabbit polyclonal anti-IgG recognized each of the known human IgG isoallotypes. These findings demonstrate "blind spots" in isoalloantibody detection by a monoclonal anti-IgG. If a patient has anti-RBC antibodies predominantly of an IgG3 subtype (the IgG3-03 and/or IgG3-13 variety), then it is possible that a clinically significant alloantibody would be missed. IgG-03 and IgG-13 have an estimated frequency of 1% to 3% in Caucasian populations and 20% to 30% in certain African populations. Nonreactivity with IgG4 is a known characteristic of this monoclonal anti-IgG, but IgG4 isoallotypes have not been previously reported

Published
2016

180. Antigen Density Dictates Immune Responsiveness following Red Blood Cell Transfusion

Author

Arthur, Connie M., primary, Patel, Seema R., additional, Smith, Nicole H., additional, Bennett, Ashley, additional, Kamili, Nourine A., additional, Mener, Amanda, additional, Gerner-Smidt, Christian, additional, Sullivan, Harold C., additional, Hale, J. Scott, additional, Wieland, Andreas, additional, Youngblood, Benjamin, additional, Zimring, James C., additional, Hendrickson, Jeanne E., additional, and Stowell, Sean R., additional

Published
2017
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184. Heterogeneity of blood processing and storage additives in different centers impacts stored red blood cell metabolism as much as storage time: lessons from REDS-III-Omics.

Author

D'Alessandro, Angelo, Culp‐Hill, Rachel, Reisz, Julie A., Anderson, Mikayla, Fu, Xiaoyun, Nemkov, Travis, Gehrke, Sarah, Zheng, Connie, Kanias, Tamir, Guo, Yuelong, Page, Grier, Gladwin, Mark T., Kleinman, Steve, Lanteri, Marion, Stone, Mars, Busch, Michael, Zimring, James C., Culp-Hill, Rachel, and Recipient Epidemiology and Donor Evaluation Study-III (REDS-III)

Subjects
BLOOD collection, BLOOD transfusion, ERYTHROCYTES, BLOOD diseases, PHENOTYPES, METHIONINE metabolism, ERYTHROCYTE metabolism, ANALYSIS of variance, BIOCHEMISTRY, COMPARATIVE studies, GLYCOLYSIS, RESEARCH methodology, MEDICAL cooperation, MULTIVARIATE analysis, RESEARCH, RESEARCH funding, TIME, EVALUATION research, IN vitro studies
Abstract

Background: Biological and technical variability has been increasingly appreciated as a key factor impacting red blood cell (RBC) storability and, potentially, transfusion outcomes. Here, we performed metabolomics analyses to investigate the impact of factors other than storage duration on the metabolic phenotypes of stored RBC in a multicenter study.Study Design and Methods: Within the framework of the REDS-III (Recipient Epidemiology and Donor Evaluation Study-III) RBC-Omics study, 13,403 donors were enrolled from four blood centers across the United States and tested for the propensity of their RBCs to hemolyze after 42 days of storage. Extreme hemolyzers were recalled and donated a second unit of blood. Units were stored for 10, 23, and 42 days prior to sample acquisition for metabolomics analyses.Results: Unsupervised analyses of metabolomics data from 599 selected samples revealed a strong impact (14.2% of variance) of storage duration on metabolic phenotypes of RBCs. The blood center collecting and processing the units explained an additional 12.2% of the total variance, a difference primarily attributable to the storage additive (additive solution 1 vs. additive solution 3) used in the different hubs. Samples stored in mannitol-free/citrate-loaded AS-3 were characterized by elevated levels of high-energy compounds, improved glycolysis, and glutathione homeostasis. Increased methionine metabolism and activation of the transsulfuration pathway was noted in samples processed in the center using additive solution 1.Conclusion: Blood processing impacts the metabolic heterogeneity of stored RBCs from the largest multicenter metabolomics study in transfusion medicine to date. Studies are needed to understand if these metabolic differences influenced by processing/storage strategies impact the effectiveness of transfusions clinically. [ABSTRACT FROM AUTHOR]

Published
2019
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185. Biliverdin Reductase B Protects Against Primaquine Induced Hemolysis - Identification of a Novel Anti-Oxidant Pathway in Murine Erythrocytes

Author

Dziewulska-Cronk, Karolina, Hay, Ariel M, D'Alessandro, Angelo, Reisz, Julie A, Garrett, Jordan, Buehler, Paul, Kao, Joseph, and Zimring, James C

Abstract

Background: Biliverdin Reductase B (BlvrB) is the fourth most abundant enzyme in red blood cells (RBCs) and is widely expressed in other tissues. In normal heme catabolism, porphyrin is converted to biliverdin-alpha (by hemoxygenase (HO)) and then reduced to bilirubin-alpha (by biliverdin reductase A (BlvrA)). Bilirubin-alpha is then glucuronidated and excreted. The large body of literature investigating heme metabolism, bilirubin-based pathologies, and the oxidative biology of bilirubin/biliverdin in adults focuses almost exclusively on BlvrA and the alpha isomers of biliverdin and bilirubin. However, porphyrin is a tetrapyrrole with 4 distinct meso-carbon bridges, each of which can be broken to generate a distinct biliverdin isomer (alpha, beta, gamma, or delta). Although HO is exquisitely specific for the alpha-bond (generating only biliverdin-alpha), chemical coupled oxidation of heme yields all four biliverdin isomers. BlvrB (and not BlvrA) can reduce each of non-alpha biliverdin isomers into their corresponding bilirubin isomers (bilirubin-beta is prevalent in neonatal jaundice and kernicterus). BlvrB also reduces flavins and additional quinone metabolites. Despite BlvrB's abundance and evolutionary conservation, its only known function is a subtle effect on hematopoietic lineage fate (megakaryocyte vs. erythroid). BlvrB has no known function in mature RBCs. We hypothesized that BlvrB plays an important antioxidant role that would only become obvious when other redundant anti-oxidant pathways were limited.

Published
2023
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186. NXPE2 Is the Target of Ter-119 When Complexed with Gypa in Mice

Author

Keele, Gregory R, Holness, Nadia, Jash, Arijita, Hay, Ariel M, Ewald, Sarah, Churchill, Gary A, D'Alessandro, Angelo, Dzieciatkowska, Monika, and Zimring, James C

Abstract

Background: Red blood cells (RBCs) have a complex biology that allows regulation of metabolism, cellular rigidity, ion exchange, pH, and molecular communication with the vasculature. A central regulator of these biologies are macrocomplexes of integral membrane proteins that are both linked to cytoskeletal proteins and also differentially bind to metabolic enzymes based upon oxygenation status of the RBC. RBC surface staining, co-immunoprecipitation, and cross-linking proteomic approaches have generated a model of the macrocomplex encompassing Band 3, Rh, RhAG, CD47, glycophorin A, glycophorin B, and LW. TER-119 is a monoclonal antibody with exquisite specificity for the erythroid lineage in mice. However, the molecular target of TER-119 has remained unknown. TER-119 immunoprecipitates 4 specific protein bands, two of which are glycophorin A (GYPA) monomers or homodimers respectively; however, TER-119 is non-reactive to GYPA when assayed through Western blots and flow cytometry with erythroid cell lines expressing GYPA. These data led the originators of TER-119 to conclude it binds to a GYPA associated protein, but not GYPA itself. In contrast, others have concluded that TER-119 binds GYPA directly, and have inferred GYPA biology based upon TER-119 reactivity.

Published
2023
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187. Mechanisms of Primaquine Induced Hemolysis in a Novel Humanized Murine Model of Mediterranean G6PD Deficiency

Author

Dziewulska-Cronk, Karolina, Reisz, Julie A, Nemkov, Travis, Hay, Ariel M, Issaian, Aaron, Cendali, Francesca, Dzieciatkowska, Monika, Gamboni, Fabia, Lamb, Derek, Palha, Mitasha, Kao, Joseph, Buehler, Paul, D'Alessandro, Angelo, Commons, Robert, and Zimring, James C

Abstract

Background: Approximately half a billion individuals are genetically deficient in glucose 6-phosphate dehydrogenase (G6PD) due to amino acid variants generally thought to decrease enzyme half-life. Decreased G6PD activity limits the antioxidant capacity of red blood cells (RBCs). As such, certain drugs that induce oxidative stress can cause life-threatening hemolysis in G6PD deficient (G6DPd) individuals. Standard regiments of the only approved drugs that can cure liver phase Plasmodium vivax ( p. vivax) (i.e. primaquine and tafenoquine) are contraindicated in G6PDd patients due to risks of hemolysis. Effective treatment of G6PDd individuals infected with p. vivaxrequires a prolonged course of primaquine (8 weeks), leading to non-adherence, and subsequent reduced efficacy and increased risk of transmission. Despite decades of research and large drug screening programs, no non-hemolytic compound has been identified that can eradicate p. vivax. Lack of progress in this area has likely been hampered by an incomplete mechanistic understanding of primaquine induced hemolysis, in part due to the lack of an animal model that recapitulates G6PD instability.

Published
2023
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188. Genetic Polymorphisms in the Ferrireductase STEAP3 Regulate a Ferroptosis-like Process of Lipid Peroxidation-Induced Hemolysis in Murine and Human Red Blood Cells

Author

D'Alessandro, Angelo, Keele, Gregory R, Hay, Ariel M, Nemkov, Travis, Stephenson, Daniel, Deng, Xutao, Stone, Mars, Kleinman, Steven, Spitalnik, Steven, Norris, Philip J, Busch, Michael Paul, Churchill, Gary A, and Zimring, James C

Abstract

Red blood cell (RBC) storage in the blood bank induces a series of biochemical and morphological alterations, collectively denoted as the storage lesion(s). Membrane damage by lipid peroxidation is a hallmark of the storage lesion, a process thought to be triggered by oxidant stress. To identify the genetics underlying this phenomenon, we leveraged a novel murine system, the Jackson lab Diversity Outbred (JDO) mouse colony, which was obtained by extensively cross-breeding 8 founder mouse strains with extreme genetically heterogeneity ( Figure 1.A). A total of 350 fresh and stored (up to 7 days) murine RBC samples were tested by mass spectrometry-based metabolomics and lipidomics. At the end of storage, post-transfusion recovery (PTR), which measures intra- and extravascular hemolysis and is a gold standard for determining RBC storage quality, was determined by quantifying the percentage of stored RBCs that were still circulating 24h after their transfusion into Ubi-GFP+ recipient mice ( Figure 1.A). Genome wide-association studies identified a strong association between PTR and a polymorphic region on chromosome 1 ( Figure 1.A), which encodes STEAP3, a ferrireductase. This region was associated with altered metabolism of stored RBCs ( Figure 1.A), especially an elevation of lipid peroxidation products (hive plot in Figure 1.A). Mechanistically, these data support a role for STEAP3 in promoting Fenton and Haber-Weiss chemistry in iron-loaded RBCs. Specifically, ferrous iron participates in this chemistry, becoming oxidized to its ferric state with concomitant generation of hydroxyl or hydroperoxyl radicals; these in turn attack fatty acids (preferentially, poly- and highly-unsaturated fatty acids, such as octadecadienoic and eicosatetraenoic acid), thereby promoting lipid peroxidation (to hydroxyoctadecadienoic (HODE) and hydroxyeicosatetraenoic (HETE) acids, respectively). By reducing Fe 3+to Fe 2+, STEAP3 can shift the balance of this reaction by increasing the availability of the reactant, thereby favoring the generation of product radicals; this process is analogous to ferroptosis, as described in other biological systems.

Published
2023
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189. Novel Humanized G6PD Deficient Mice Reveal Mechanisms of Increased Tolerance to Exercise As Gleaned By Multi-Omics in Models of Critical Speed

Author

Cendali, Francesca, Dzieciatkowska, Monika, Lisk, Christina, Irwin, David, Zimring, James C, Dziewulska-Cronk, Karolina, Nemkov, Travis, and D'Alessandro, Angelo

Abstract

INTRODUCTION:Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is the most common enzymatic deficiency in humans, affecting ~500 million people or ~6% of mankind. G6PD is the rate limiting enzyme of the pentose phosphate pathway (PPP), the main antioxidant pathway in mature red blood cells (RBCs). Activation of the PPP generates NADPH, an essential reducing equivalent for antioxidant metabolism that protects against intra- and extra-vascular hemolysis in response to oxidant stress. Impaired G6PD activity makes RBCs susceptible to hemolysis induced by oxidant challenges. Exercise-induced oxidant stress is a well-established concept in the field of physiology. Individuals with G6PD deficiency are recommended to refrain from strenuous exercise, as they are deemed to be at increased risk for hemolytic events in response to exercise-induced oxidant stress. While biochemically sound, this rationale has never been tested mechanistically, owing to ethical and technical limitations. As such, knowledge is limited regarding molecular impacts of exercise activity in G6PD deficient individuals.

Published
2023
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190. Metabolomics of AS-1 RBC storage

Author

Roback, John D., Josephson, Cassandra D., Waller, Edmund K., Newman, James L., Karatela, Sulaiman, Uppal, Karan, Jones, Dean, Zimring, James C., and Dumont, Larry J.

Subjects
Erythrocytes, Adenine, Cell Membrane, Sodium Chloride, Lipids, Article, Gas Chromatography-Mass Spectrometry, Mice, Inbred C57BL, Kinetics, Mice, Oxidative Stress, Glucose, Blood Preservation, Tandem Mass Spectrometry, Metabolome, Animals, Humans, Mannitol, Erythrocyte Transfusion, Glycolysis, Chromatography, Liquid, Signal Transduction
Abstract

Population-based investigations suggest that red blood cells (RBCs) are therapeutically effective when collected, processed, and stored for up to 42 days under validated conditions before transfusion. However, some retrospective clinical studies have shown worse patient outcomes when transfused RBCs have been stored for the longest times. Furthermore, studies of RBC persistence in the circulation after transfusion have suggested that considerable donor-to-donor variability exists and may affect transfusion efficacy. To understand the limitations of current blood storage technologies and to develop approaches to improve RBC storage and transfusion efficacy, we investigated the global metabolic alterations that occur when RBCs are stored in AS-1 (AS1-RBC). Leukoreduced AS1-RBC units prepared from 9 volunteer research donors (12 total donated units) were serially sampled for metabolomics analysis over 42 days of refrigerated storage. Samples were tested by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, and specific biochemical compounds were identified by comparison to a library of purified standards. Over 3 experiments, 185 to 264 defined metabolites were quantified in stored RBC samples. Kinetic changes in these biochemicals confirmed known alterations in glycolysis and other pathways previously identified in RBCs stored in saline, adenine, glucose and mannitol solution (SAGM-RBC). Furthermore, we identified additional alterations not previously seen in SAGM-RBCs (eg, stable pentose phosphate pathway flux, progressive decreases in oxidized glutathione), and we delineated changes occurring in other metabolic pathways not previously studied (eg, S-adenosyl methionine cycle). These data are presented in the context of a detailed comparison with previous studies of SAGM-RBCs from human donors and murine AS1-RBCs. Global metabolic profiling of AS1-RBCs revealed a number of biochemical alterations in stored blood that may affect RBC viability during storage as well as therapeutic effectiveness of stored RBCs in transfusion recipients. These results provide future opportunities to more clearly pinpoint the metabolic defects during RBC storage, to identify biomarkers for donor screening and prerelease RBC testing, and to develop improved RBC storage solutions and methodologies.

Published
2014

191. Scientific advances: Fallacy of perfection harms peer review

Author

Zimring, James C. and Spitalnik, Steven L.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): James C. Zimring (corresponding author) [1]; Steven L. Spitalnik [2] Voltaire wrote in 1772, 'the best is the enemy of the good', warning against the fallacy that something is [...]

Published
2016
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199. Bridging channel dendritic cells induce immunity to transfused red blood cells

Author

Calabro, Samuele, primary, Gallman, Antonia, additional, Gowthaman, Uthaman, additional, Liu, Dong, additional, Chen, Pei, additional, Liu, Jingchun, additional, Krishnaswamy, Jayendra Kumar, additional, Nascimento, Manuela Sales L., additional, Xu, Lan, additional, Patel, Seema R., additional, Williams, Adam, additional, Tormey, Christopher A., additional, Hod, Eldad A., additional, Spitalnik, Steven L., additional, Zimring, James C., additional, Hendrickson, Jeanne E., additional, Stowell, Sean R., additional, and Eisenbarth, Stephanie C., additional

Published
2016
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200. Metabolites in stored platelets associated with platelet recoveries and survivals

Author

Zimring, James C., primary, Slichter, Sherrill, additional, Odem-Davis, Katherine, additional, Felcyn, Jacob R., additional, Kapp, Linda M., additional, Bell, Lauren N., additional, Gunst, P. Ross, additional, Corson, Jill, additional, Jones, Mary Kay, additional, Pellham, Esther, additional, Bailey, S. Lawrence, additional, and Fu, Xiaoyun, additional

Published
2016
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